Article, Emergency Medicine

Safety of parenteral ketorolac use for analgesia in geriatric emergency department patients

a b s t r a c t

Objective: To assess the safety of a single dose of parenteral ketorolac for analgesia management in Geriatric EMer- gency department (ED) patients.

Methods: This was a retrospective study of all administrations of parenteral ketorolac to adults >=65 years of age and matched controls. The primary outcome was the occurrence of any of the following adverse events within 30 days of the ED visit: gastrointestinal bleeding, intracranial bleeding, acute decompensated heart failure, acute coronary syndrome, dialysis, transfusion, and death. The secondary outcome was the occurrence of an in- crease in serum creatinine of >=1.5 times baseline within 7 and 30 days of the ED visit.

Results: There were 480 patients included in the final analysis, of which 120 received ketorolac (3: 1 matching). The primary outcome occurred in 14 of 360 patients who did not receive ketorolac and 2 of 120 ketorolac patients (3.9% vs 1.7%, p = 0.38; OR 2.39, 95% CI 0.54-10.66). There was no occurrence of dialysis or death in either group. The secondary outcome occurred in 1 of 13 and 1 of 23 ketorolac patients with both a baseline serum creatinine and a measure within 7 and 30 days, respectively, but did not occur in patients who did not receive ketorolac (7 days: 7.7% vs 0.0%, p = 0.29; 30 days: 4.4% vs 0.0%, p = 0.22).

Conclusion: The use of single doses of parenteral ketorolac for analgesia management was not associated with an increased incidence of adverse cardiovascular, gastrointestinal, or renal adverse outcomes in a select group of older adults.

(C) 2019

Introduction

With the rapidly increasing population of individuals aged 65 years and older, decision making in the emergency department (ED) regard- ing pain management has become much more complex. Older adults have an increased susceptibility to adverse effects, polypharmacy, and comorbid medical conditions. Currently, the geriatric patient population makes up approximately 20% of all ED visits and requires hospital ad- mission more frequently than any other age group [1]. Pain is a highly prevalent and commonly reported symptom, with older adults experiencing pain in approximately 40-50% of all ED visits [2-5]. De- spite this, Geriatric patients often receive significantly lower doses of an- algesia than younger adults and may not even receive analgesia in the ED, which can lead to poor or inadequate pain management and subop- timal patient outcomes [3]. Detrimental consequences of poor pain management include worse health status, functional and sleep impair- ment, falls, depression, decreased appetite, social isolation, and

* Corresponding author at: Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

E-mail address: [email protected] (A.E. Mattson).

increased Healthcare costs [6,7]. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ketorolac, are one of the most commonly used Medication classes for the treatment of pain and inflammation but are often avoided in older adults due to the concern for significant adverse effects, notably those gastrointestinal, cardiovascular, and renal in nature [8-13]. The American Geriatrics Society Beers criteria for potentially inappropriate medication (PIM) Use in Older Adults was developed to aid in the prevention of the use of high-risk medica- tions such as opioids and NSAIDs to decrease the risk of adverse effects [14]. According to this list, there is a strong recommendation to avoid ketorolac in older adults due to the increased risk of gastrointestinal bleeding, Peptic ulcer disease, exacerbation of heart failure, and acute kidney injury. Additionally, opioids also have a strong recommendation against use given their increased central nervous system effects in older adults [14]. The recommendation to avoid ketorolac, however, doesn’t provide any guidance on whether single doses for acute pain manage- ment are acceptable and safe.

Literature on optimal ED pain management in the geriatric popula- tion is extremely limited at present. With the current opioid epidemic and concern for central nervous system and respiratory adverse effects

https://doi.org/10.1016/j.ajem.2019.06.009

0735-6757/(C) 2019

728 G.L. Anderson et al. / American Journal of Emergency Medicine 38 (2020) 727730

of opioids, NSAIDs could play an important role in the provision of acute analgesia, specifically in the geriatric patient population [15]. To our knowledge, this is the first study focusing on the incidence of adverse ef- fects related to acute, single doses of parenteral ketorolac in geriatric ED patients. The goal of this study was to assess whether a single use of par- enteral ketorolac for analgesia management contributes to adverse car- diovascular, gastrointestinal, and renal outcomes in geriatric ED patients.

Methods

Study design and setting

A single-center, Observational retrospective cohort study was con- ducted using Electronic Medical Record data from geriatric patients who presented to the ED from January 1, 2017 through December 31, 2017. The study setting was an academic medical center with an annual ED census of approximately 77,000 visits, including approximately 25,000 visits by patients 65 years of age and older. The study was reviewed and approved by our Institutional Review Board.

Selection of participants

We included patients 65 years of age and older who presented to the ED during the study period and received parenteral (intramuscular or intravenous) ketorolac for analgesia management prior to being discharged home from the ED with self-care. We excluded patients who required hospital admission, declined authorization for use of medical record for research, and lacked follow-up within our health system.

Direct 3: 1 matching was used to match patients who did not receive parenteral ketorolac to those who did receive parenteral ketorolac based on age +- 2 years; gender; baseline renal function (stage of renal disease); and history of gastrointestinal bleeding, coronary artery disease, congestive heart failure, and liver disease. While we did not di- rectly match on cancer and anticoagulant use, these factors remained balanced between groups. Anticoagulant use was defined as the outpa- tient use of any of the following anticoagulants: warfarin, apixaban, edoxaban, rivaroxaban, dabigatran, enoxaparin, fondaparinux, or sub- cutaneous heparin.

Outcomes

The primary outcome was a patient important outcome that in- cluded the occurrence of any of the following events within 30 days of the ED visit: gastrointestinal bleeding, intracranial bleeding, acute de- compensated heart failure, acute coronary syndrome, dialysis, transfu- sion, and death. Gastrointestinal bleeding, intracranial bleeding, acute decompensated heart failure, and acute coronary syndrome were iden- tified via the use of ICD 10 Diagnosis codes. Transfusion was defined as requirement of a minimum of 1 unit of red blood cells. The secondary outcome was the occurrence of an increase in serum creatinine of >=1.5 times baseline within 7 and 30 days of the ED visit. We considered this to be a clinically significant increase in serum creatinine based on the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Prac- tice Guideline for Acute Kidney Injury [16]. Baseline serum creatinine was either the measured serum creatinine the day of ketorolac admin- istration or within 30 days prior to the ED visit. Patients were included in this analysis if they had available follow-up Serum creatinine measurements.

Data analysis

Descriptive statistics are reported using counts and percentages. In- dividual outcomes of interest were compared between groups using Fisher’s exact tests, and logistic regression was used to compare the

Composite outcome of having any event within 30 days between groups. Due to the limited number of events, conditional logistic regres- sion was not used. A p value <=0.05 was considered to be statistically sig- nificant. Analyses were performed by a biostatistician with expertise in pharmaceutical studies. All analyses were done using SAS version 9.4 (SAS Institute, Inc.; Cary, NC).

Results

Characteristics of study subjects

During the study period, there were 24,529 ED visits by adults 65 years of age and older, and 57.3% were admitted. Among the 10,474 visits that resulted in patients being discharged from the ED, 8.6% of the visits were by patients who did not authorize for medical re- cord review. Further, after excluding those visits by patients without a primary care provider in our health system or lack of reliable follow- up, the final cohort comprised 4906 ED visits by 2303 unique patients. Among these, there were 120 patients who received parenteral ketorolac, representing 5.2% of the cohort. After direct 3: 1 matching, our final sample included 480 geriatric ED patients. Parenteral ketorolac was administered to 120 patients; 360 patients did not receive paren- teral ketorolac (Fig. 1).

Patient baseline characteristics are described in Table 1. Overall, pa- tients who received ketorolac in the ED were relatively healthy with a low prevalence of comorbidities. Only 4.2% of patients in each group had a past medical history of chronic kidney disease, which was uni- formly classified as stage 3. All ketorolac doses were administered intra- venously; no patients received intramuscular ketorolac. Additionally, most patients received the recommended ketorolac dose of 15 mg, with only 7 patients receiving a ketorolac dose of 30 mg.

Excluded

Required hospital admission (n = 14,055) Declined research authorization (n = 901) Lacked follow-up within system (n = 7,270)

ED visits by adult patients

>=65 years of age from 01/01/17 through 12/31/17

(n = 24,529)

3:1 direct matching

4,906 ED visits by 2,303 unique patients No ketorolac (n = 2,183)

Ketorolac (n = 120)

Ketorolac (n = 120)

No ketorolac (n = 360)

Study cohort (n = 480)

Fig. 1. Study design.

G.L. Anderson et al. / American Journal of Emergency Medicine 38 (2020) 727730 729

Table 1

Patient baseline characteristics

Variable No ketorolac

(n = 360)

Ketorolac (n = 120)

adverse effects of opioids, our goal was to assess whether or not a single dose of parenteral ketorolac contributes to adverse cardiovascular, gas- trointestinal, and renal outcomes in geriatric ED patients. Overall in our ED, the administration of ketorolac was infrequent in older adults, with

Age, mean (SD), years 72.2 (5.8) 72.2 (5.8)

Female gender, % 213 (59.2) 65 (54.2)

Chronic kidney disease stage 3, % 15 (4.2) 5 (4.2)

History of gastrointestinal bleeding, % 3 (0.8) 1 (0.8)

history of coronary artery disease, % 99 (27.5) 33 (27.5)

History of congestive heart failure, % 27 (7.5) 9 (7.5)

History of liver disease, % 9 (2.5) 3 (2.5)

History of cancer, % 35 (9.7) 11 (9.2)

Anticoagulant use, % 35 (9.7) 9 (7.5)

Main results

Overall, observed Adverse event rates within the 30 days following the ED visit were very low but higher in the group who did not receive parenteral ketorolac. The primary outcome occurred in 14 of 360 pa- tients who did not receive parenteral ketorolac and 2 of 120 patients who received parenteral ketorolac (3.9% vs 1.7%, p = 0.38; OR 2.39, 95% CI 0.54-10.66) (Table 2). Both events in the ketorolac group were gastrointestinal bleeding; the first patient developed upper gastrointes- tinal bleeding secondary to suspected peptic ulcer disease from signifi- cant chronic NSAID ingestion, and the second patient developed lower gastrointestinal bleeding secondary to radiation proctopathy. The most frequently observed adverse event was acute decompensated heart failure, occurring in 7 of 360 patients who did not receive paren- teral ketorolac and 0 of 120 patients who received parenteral ketorolac (1.9% vs 0.0%, p = 0.20). The next most frequently observed adverse event was the requirement of transfusion, occurring in 5 patients who did not receive parenteral ketorolac and 0 of 120 patients who received parenteral ketorolac (1.4% vs 0.0%, p = 0.34). Requirement of transfu- sion was related to post-procedure bleeding, myelodysplastic syn- drome, or chemotherapy-induced anemia. There was no occurrence of dialysis or death in either group. Secondary outcome data are limited to those patients who had both a baseline serum creatinine and a mea- sure within 7 or 30 days of the ED visit. The secondary outcome, an in- crease in serum creatinine of >=1.5 times baseline, occurred within 7 days in 0 of 32 patients who did not receive parenteral ketorolac and 1 of 13 patients who received parenteral ketorolac (0.0% vs 7.7%, p = 0.29) and within 30 days in 0 of 81 patients who did not receive parenteral ketorolac and 1 of 23 patients who received parenteral ketorolac (0.0% vs 4.4%, p = 0.22).

Discussion

To our knowledge, this is the first and largest study to date to assess the safety of parenteral Ketorolac use for analgesia management in geri- atric ED patients. With the changing approach to optimal ED pain man- agement in the Geriatric population along with the current opioid epidemic and concern for central nervous system and respiratory

Table 2

Primary outcome

Event

No ketorolac (n = 360)

Ketorolac (n = 120)

p value

Composite of any event within 30 days, %

14 (3.9)

2 (1.7)

0.38

Gastrointestinal bleeding, %

0 (0.0)

2 (1.7)

0.06

Intracranial bleeding, %

1 (0.3)

0 (0.0)

1.00

Acute decompensated heart failure, %

7 (1.9)

0 (0.0)

0.20

Acute coronary syndrome, %

1 (0.3)

0 (0.0)

1.00

Dialysis, %

0 (0.0)

0 (0.0)

Transfusion, %

5 (1.4)

0 (0.0)

0.34

Death, %

0 (0.0)

0 (0.0)

5.2% receiving it. After matching for age, gender, and comorbidities, we did not find an increase in the incidence of adverse outcomes following the use of single doses of parenteral ketorolac for analgesia manage- ment. There was a higher occurrence of the primary patient important outcome of a composite of any adverse event within the 30 days follow- ing the ED visit in the group who did not receive parenteral ketorolac (3.9% vs 1.7%; OR 2.39, 95% CI 0.54-10.66).

Literature on optimal ED pain management strategies and the ad- ministration of NSAIDs such as ketorolac for acute pain in geriatric ED patients is currently scarce, and thus little is known regarding the fre- quency of associated adverse effects and outcomes. A post marketing surveillance study conducted by Strom et al. evaluated the risk of gas- trointestinal and operative site bleeding associated with the use of par- enteral ketorolac compared to parenteral opioids in hospitalized patients [17]. Gastrointestinal bleeding occurred in 4% of ketorolac pa- tients compared to 3.6% of opioid patients (OR 1.30; 95% CI 1.11-1.52), and operative site bleeding occurred in 39.6% of ketorolac patients compared to 38.6% of opioid patients (OR 1.02; 95% CI 0.95-1.10). The risk of gastrointestinal and operative site bleeding in- creased with age in both groups, but more so in the ketorolac group than the opioid group, and higher doses of ketorolac were also associ- ated with increased bleeding risk. For ketorolac therapy lasting 5 or fewer days, there was only a small increased risk of gastrointestinal bleeding (OR 1.17; 95% CI 0.99-1.39), but the risk increased to 2.20 (95% CI 1.36-3.57) when therapy was prolonged beyond 5 days. Overall, the authors found a small association between ketorolac use and both gastrointestinal and operative site bleeding but did find a larger, clini- cally important risk associated with ketorolac use in high doses, older subjects, and for prolonged therapy [17]. In our ED, it is not routine prac- tice to dismiss patients home with ketorolac, particularly older adults. A retrospective cohort study comparing the risk for acute renal failure as- sociated with parenteral ketorolac versus parenteral opioids in hospital- ized patients found acute renal failure occurred in 1.07% of ketorolac patients compared to 1.11% of opioid patients [18]. The risk for acute renal failure increased with age (rate ratio 1.37 per 10-year increase in age), and acute renal failure associated with ketorolac versus opioids was increased with durations of therapy longer than 5 days (rate ratio 2.08). Overall, the authors concluded that the incidence of acute renal failure with parenteral ketorolac is low and no greater than that with parenteral opioids when administered for 5 days or less, but may be as- sociated with an increased incidence of acute renal failure when given for N5 days [18].

Although these studies were large in size and provided data on the incidence of gastrointestinal and operative site bleeding and acute renal failure with the use of ketorolac, they included patients of all ages and assessed longer durations of therapy. Our study is unique in that it focused solely on the geriatric population to provide more spe- cific data on the safety and incidence of adverse effects related to acute, single doses of ketorolac. Due to the push to decrease opioid use in light of the current opioid epidemic, EDs are working to find safe, alternative analgesic agents. At our hospital, we frequently utilize ketorolac over opioids for pain management, most commonly at a dose of 15 mg given the evidence supporting the use of lower doses (10 or 15 mg) versus 30 mg doses [19]. Additionally, our study not only assessed the gastrointestinal and renal adverse effects of ketorolac but also included cardiovascular outcomes.

Our results are dependent upon the accuracy of ICD codes and the information documented in the electronic medical record. Provider’s bias towards selection of patients could have been present throughout the study period, however, we attempted to account for confounding variables and differences in baseline patient characteristics by utilizing direct matching with a cohort seen during the same time period. Our

730 G.L. Anderson et al. / American Journal of Emergency Medicine 38 (2020) 727730

sample size was limited by the number of patients discharged with re- liable follow-up data available for at least 30 days. To maintain homoge- neity, we only included patients discharged home from the ED who received follow-up care within our health system. Because of the rigor- ous inclusion and exclusion criteria, we had a relatively small sample size. This increases our internal validity but decreases the external valid- ity of the results, however, this is still the largest number of patients evaluated to date assessing the safety of parenteral ketorolac use in ge- riatric ED patients. Additionally, we were unable to extract the chief complaint or reason for receiving ketorolac. This could skew the data as ketorolac is generally used for more mild and self-limiting conditions such as renal colic and Muscle pain while opioids are commonly given for more severe conditions such as fractures. The patients that received ketorolac also appear to have a lower number of comorbidities than our average older adult, so the results are applicable to low-risk, healthier patients which limits the generalizability to all geriatric patients. This is likely attributed to the decision making process of clinicians to utilize ketorolac in patients that appear to be healthy with fewer risk factors, and differences in analgesia choice are also driven by the type of pre- senting pain [20]. Another limitation is that this is a single-center study, and our older population is 80% white race. Furthermore, NSAIDs are over-the-counter, and it is likely that some patients were taking them at home and this was not reported on their medication list and therefore we were not able to account for this in the analysis. Lastly, our secondary outcome was an increase in serum creatinine as defined by the KDIGO guidelines, however, the comprehensive definition of acute renal failure was not included [16].

Conclusions

In summary, this study found no associated increase in the incidence of adverse cardiovascular, gastrointestinal, and renal outcomes with the use of single doses of parenteral ketorolac for acute analgesia manage- ment in select geriatric ED patients. Emergency medicine providers should consider the use of parenteral ketorolac in low-risk geriatric pa- tients to help limit opioid use and the suboptimal patient outcomes caused by inadequate pain management.

Funding

This work was funded in part by a grant from the Mayo Clinic De- partment of Pharmacy.

Declaration of Competing Interest

The authors have no conflicts of interest to disclose.

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